Regulation of Neural Migration During Brain Development

大脑发育过程中神经迁移的调节

基本信息

批准号：
10361457
负责人：
Martin Miguel Riccomagno
金额：
$ 33.04万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-15 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361457
关键词：
Ablation Adaptor Signaling Protein Address Adhesions Adhesives Affect Amino Acid Motifs Automobile Driving Axon BCAR1 gene Behavior Behavioral Biochemical Biochemistry Brain Cell Adhesion Cell Adhesion Molecules Cell-Cell Adhesion Cells Cerebral cortex Cobblestone Lissencephaly Cognition Cortical Dysplasia Cues Data Defect Development Developmental Process Electroencephalography Epilepsy Epileptogenesis Etiology Extracellular Matrix Family Focal Adhesions Foundations Genes Genetic In Vitro Instruction Knockout Mice Knowledge Laminin Learning Disabilities Ligands Link Mediating Mission Modeling Molecular Muscle fasciculation Mutation Nervous system structure Neurodevelopmental Disorder Neuroglia Neurons Pathway interactions Patients Perception Perceptual learning Phenotype Phosphorylation Physiological Physiology Play Process Public Health Publishing Radial Regulation Research Resistance Role Signal Pathway Signal Transduction Signaling Molecule Stratification Testing Time Tissues United States National Institutes of Health Work autism spectrum disorder brain abnormalities cell motility comorbidity conditional knockout developmental disease effective therapy epileptic encephalopathies experimental study in vivo insight lissencephaly live cell imaging migration mouse genetics mutant neural circuit neurodevelopment neuromechanism neuroregulation novel protein function receptor relating to nervous system scaffold tool

项目摘要

The proposed studies will identify mechanisms through which Cas adaptor proteins regulate cortical development and function. Accurate cell migration and lamination are indispensable for the development of a functional nervous system. Congenital disruption of any of these processes can result in neurodevelopmental disorders ranging from lissencephaly to autism-spectrum disorders. During multiple developmental steps, neurons are guided by repulsive and attractive cues, while actively interacting with the extracellular matrix (ECM) and other cells. Although much is known about the ligand-receptor pairs required for these cues to regulate cell trajectories, it remains unknown how instructive and adhesive cues are integrated and interpreted within the neuron. The Cas (Crk associated substrate) family of cytosolic adaptor proteins are known to signal downstream of several neural guidance cues, and regulate focal adhesion turnover. Using Cas proteins as a model, we have a unique opportunity to broaden our understanding of how instructive and permissive signaling pathways converge during neural development to regulate cell adhesion. To test the hypothesis that Cas proteins are essential for coordinating cortical lamination and migration, experiments will be organized into three Specific Aims. Guided by strong preliminary data showing that ablation of Cas genes results in cortical defects that resemble cobblestone lissencephaly, Aim 1 will establish, for the first time, the functional requirement for Cas proteins during cortical migration and lamination. Aim 2 will explore the contributions of Cas-mediated cortical scaffold formation to physiology and behavior, using EEG and behavioral approaches. Aim 3 will test how regulation of Cas function affects cortical lamination. These experiments will provide new knowledge on the basic mechanisms underlying the establishment of neural circuits essential for perception and cognition.

拟议的研究将确定CAS适配器蛋白调节皮质的机制发展和功能。准确的细胞迁移和层压对于发展是必不可少的功能性神经系统。这些过程中任何一个过程的先天性破坏都可能导致神经发育从Lissencephaly到自闭症谱系疾病的疾病。在多个发展步骤中，神经元以排斥性和吸引人的提示为指导，同时与细胞外基质积极相互作用（ECM）和其他细胞。尽管这些提示需要的配体对配体对调节细胞轨迹，尚不清楚如何整合和解释启发性和粘合性线索在神经元内。已知CAS（CRK相关的基板）胞质衔接蛋白家族发出信号几个神经引导线索的下游，并调节局灶性粘附周转率。使用CAS蛋白作为模型，我们有一个独特的机会来扩大我们对具有启发性和宽松信号的理解途径在神经发育过程中融合以调节细胞粘附。测试CAS的假设蛋白质对于协调皮质层压和迁移至关重要，实验将被组织到三个具体目标。在强大的初步数据的指导下，表明CAS基因的消融导致皮质类似于鹅卵石Lissencephaly的缺陷，AIM 1将首次建立功能性皮质迁移和层压过程中CAS蛋白的需求。 AIM 2将探讨使用脑电图和行为方法，CAS介导的皮质支架形成生理和行为。 AIM 3将测试CAS功能的调节如何影响皮层层压。这些实验将提供新的了解建立神经回路的基本机制的知识和认知。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ExBoX - a simple Boolean exclusion strategy to drive expression in neurons.

DOI：
10.1242/jcs.257212
发表时间：
2021-10-15
期刊：
Journal of cell science
影响因子：
4
作者：
Ubina T;Vahedi-Hunter T;Agnew-Svoboda W;Wong W;Gupta A;Santhakumar V;Riccomagno MM
通讯作者：
Riccomagno MM

An adhesion signaling axis involving Dystroglycan, β1-Integrin, and Cas adaptor proteins regulates the establishment of the cortical glial scaffold.

DOI：
10.1371/journal.pbio.3002212
发表时间：
2023-08
期刊：
PLOS BIOLOGY
影响因子：
9.8
作者：
Wong, Wenny;Estep, Jason A.;Treptow, Alyssa M.;Rajabli, Niloofar;Jahncke, Jennifer N.;Ubina, Teresa;Wright, Kevin M.;Riccomagno, Martin M.
通讯作者：
Riccomagno, Martin M.